Apoptotic response to albumin overload: proximal vs. distal/collecting tubule cells.

ABSTRACT

End-stage renal disease due to proteinuric states has a great impact on the quality of life by necessitating renal replacement therapy. Understanding the pathophysiologic consequences of proteinuria is crucial in order to develop treatment strategies to halt the progression. We have previously reported that cultured porcine proximal tubule cells respond to albumin overload by undergoing apoptosis. In this study, we investigated the differential apoptotic response to albumin in HKC-8 (proximal tubule) and MDCK (collecting/distal tubule) cells under high concentrations of albumin simulating the nephrotic milieu. Our results are consistent with marked cytotoxicity and apoptosis within 24 h of albumin incubation in HKC-8 cells that was closely related to the fatty acid content of the albumin. In contrast, in MDCK cells, albumin stimulated cell turnover by stimulating proliferation and late onset apoptosis regardless of the fatty acid content. Another important result of this study is the direct demonstration of albumin uptake by MDCK cells mediated by endocytosis via clathrin-coated pits. A comparison of albumin uptake between proximal and distal/collecting tubule cells revealed faster uptake in proximal tubule cells within 15 min but almost 100% albumin uptake of both cell types in 1 h. In summary, our findings demonstrate that both proximal and distal nephron segments are affected in proteinuric states, but the degrees of susceptibility to albumin and associated lipid moieties are distinct in the different nephron segments.